Osteogenic effect of magnesium oxychloride cement modified with phytic acid and loaded with strontium ranelate.

BACKGROUND: Magnesium oxychloride cement has good mechanical properties, but poor water resistance. METHODS: Phytic acid, which can form chelate with Mg2+, was used to modify magnesium oxychloride cement, and the effects of phytic acid on the strength, in vitro degradation and biological activity of magnesium oxychloride cement were studied. Based on the preparation of phytic acid modified magnesium oxychloride cement with good water resistance and biological activity, osteoporosis treatment strontium ranelate was loaded on phytic acid- magnesium oxychloride cement, strontium ranelate/phytic acid-magnesium oxychloride cement was prepared. RESULTS: It was found that the compressive strength of 1.25 wt% phytic acid-magnesium oxychloride cement after soaking in SBF for 28 d could reach 40.5 ± 2.0 MPa, 13.33% higher than that of the control group (when phytic acid was 0 wt%), and the mass loss rate of all ages was lower than that of the control group. The water resistance of magnesium oxychloride cement was effectively improved by phytic acid. After loading with strontium ranelate, the water resistance of 1.25 wt% phytic acid-magnesium oxychloride cement was improved. Cell experiments showed that strontium ranelate could effectively promote cell proliferation and improve the expression of osteoblast-related proteins. When strontium ranelate/phytic acid-magnesium oxychloride cement samples were implanted subcutaneously in rats for 4 w, no obvious inflammatory response was observed, and the material was tightly bound to the surrounding tissues. When bone cement was implanted into rat femur for 4 w, the bone cement was gradually wrapped and absorbed by new bone tissue, which grew from the outside to the inside, indicating that the bone cement containing strontium ranelate/phytic acid-magnesium oxychloride cement had excellent bone-forming ability. CONCLUSIONS: In conclusion, the results indicated that strontium ranelate/phytic acid-magnesium oxychloride cement composite bone cement had a potential application prospect in clinical bone repair.

Retrospective study on the efficacy of bisphosphonates in tyrosine kinase inhibitor-treated patients with non-small cell lung cancer exhibiting bone metastasis.

Bisphosphonates (Bps) inhibit the maturation of osteoclasts and suppress the adhesion of cancer cells to the bone matrix. They are recommended as the standard treatment for tumors exhibiting bone metastasis (BM). However, whether Bps can improve the prognosis of patients with tyrosine kinase inhibitor (TKI)-treated non-small cell lung cancer (NSCLC) exhibiting BM remains unclear. A total of 129 patients with NSCLC initially diagnosed with BM at The First Affiliated Hospital of Sun Yat-Sen University (Guangzhou, China) between January 2005 and December 2017 were analyzed in the present retrospective study. Median progression free survival (mPFS) time, median bone metastasis overall survival (mBM-OS) time and bone-associated progression-free survival were analyzed. Among the 129 patients, patients treated with Bps experienced significantly prolonged PFS time [mPFS: 7.1 vs. 5.1 months; hazard ratio (HR), 0.51; confidence interval (CI), 0.30-0.87; P=0.0114] in comparison with patients not treated with Bps. Of the 49 patients treated with frontline TKIs (EGFR TKIs or ALK TKI), 32 received Bps at the same time, while 17 patients received TKIs alone. The results revealed that mPFS time was significantly greater in the TKIs plus Bps group than in the TKIs alone group (mPFS: 11.2 vs. 6.9 months; HR, 0.13; CI, 0.05-0.35; P<0.0001). Significantly prolonged BM-OS time was also observed in the combination group in comparison with the TKIs alone group (mBM-OS: 31 vs. 22 months; HR, 0.31; CI, 0.10-0.96; P=0.0413). The present study demonstrated that among the patients who received TKIs (EGFR TKIs or ALK TKIs), those who also received Bps experienced significantly longer PFS time and tended to exhibit significantly improved BM-OS time, which indicated that Bps should be added to the treatment regimen of patients with NSCLC exhibiting genetic mutations and bone metastasis who have been prescribed TKIs (EGFR TKIs or ALK TKIs).

Deciphering Microenvironment of NSCLC based on CD8+ TIL Density and PD-1/PD-L1 Expression.

Purpose: To determine whether distinct tissue immune microenvironments differentially impact on clinical outcome in non-small cell lung cancer (NSCLC), an extended analysis of PD-1/PD-L1 and Tumor Infiltrating Lymphocytes (TILs) was performed. Materials and Methods: 1016 NSCLC mRNA-sequence samples from The Genome Data Analysis Center (TCGA) and 275 NSCLC mRNA-microarray samples from Gene Expression Omnibus (GEO) were included as testing cohort and validation cohort respectively. Enrichment scores of CD8+ T cells' metagene were used for quantifying its infiltrating density. Based on the median values of CD8+ T cell density and PD-1/PD-L1 mRNA expression, the samples were classified into four Tumor Immune Microenvironment types (TIMTs). Overall survival, as well as clinicopathological features, mutational profiles, mismatch repair score etc. were compared across the four types. Results: Neither PD-1 expression nor PD-L1 expression was associated with outcome in the overall NSCLC. Classification of TIMT based on PD-1/PD-L1 and CD8+ TIL could efficiently classify patients of different survival in ADC but not SCC, with the best overall survival achieved in TIMT3 (high CD8+ TIL and low PD-1/PD-L1), whereas TIMT2 (low CD8+ TIL and high PD-1/PD-L1) manifested the worst outcome. TIMT classification based on PD-1/ CD8+ TIL could better stratify patient of different prognosis than PD-L1/ CD8+ TIL based classification. EGFR wide type and IFNγ overexpression were associated with TIMT4 (high PD-1/PD-L1 and high CD8+ TIL), whereas tumor mutational burden (TMB) manifested no significant difference across four TIMTs. Conclusion: The classification of tumors into four microenvironment subtypes based on PD-1/PD-L1 status and CD8+ TIL is an appropriate approach to stratify patients of different clinical outcome and better guide the practical use of immunotherapy.

Value of combining serum carcinoembryonic antigen and PET/CT in predicting EGFR mutation in non-small cell lung cancer.

BACKGROUND: We sought to investigate the associations between pretreatment serum Carcinoembryonic antigen (CEA) level, 18F-Fluoro-2-deoxyglucose (18F-FDG) uptake value of primary tumor and epidermal growth factor receptor (EGFR) mutation status in non-small cell lung cancer (NSCLC). METHODS: We retrospectively reviewed medical records of 210 NSCLC patients who underwent EGFR mutation test and 18F-FDG positron emission tomography/computed tomography (PET/CT) scan before anti-tumor therapy. The associations between EGFR mutations and patients' characteristics, serum CEA, PET/CT imaging characteristics maximal standard uptake value (SUVmax) of the primary tumor were analyzed. Receiver-operating characteristic (ROC) curve was used to assess the predictive value of these factors. RESULTS: EGFR mutations were found in 70 patients (33.3%). EGFR mutations were more common in high CEA group (CEA ≥7.0 ng/mL) than in low CEA group (CEA <7.0 ng/mL) (40.4% vs. 27.6%; P=0.05). Females (P<0.001), non-smokers (P<0.001), patients with adenocarcinoma (P<0.001) and SUVmax <9.0 (P=0.001) were more likely to be EGFR mutation-positive. Multivariate analysis revealed that gender, tumor histology, pretreatment serum CEA level, and SUVmax were the most significant predictors for EGFR mutations. The ROC curve revealed that combining these four factors yielded a higher calculated AUC (0.80). CONCLUSIONS: Gender, histology, pretreatment serum CEA level and SUVmax are significant predictors for EGFR mutations in NSCLC. Combining these factors in predicting EGFR mutations has a moderate diagnostic accuracy, and is helpful in guiding anti-tumor treatment.

In vitro effects of N-acetylcysteine alone and combined with tigecycline on planktonic cells and biofilms of Acinetobacter baumannii.

BACKGROUND: Acinetobacter baumannii (A. baumannii), as a common opportunistic pathogen, has strong ability to form biofilms, which has led to drug resistance and chronic infections. The combination of N-acetylcysteine (NAC) and tigecycline (TGC) was demonstrated to synergistically inhibit biofilm-associated bacterial infections, including methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis. The purpose of this study is to investigate the effect of NAC and TGC on planktonic cells and biofilms of A. baumannii. METHODS: Minimum inhibitory concentrations (MICs) of NAC were determined by broth microdilution method. Biofilm susceptibility was assessed by crystal violet stain. Interactive effects of NAC and TGC on planktonic cells were determined by checkerboard MIC assay. Viable cell count was used to evaluate the combined effect of NAC and TGC on biofilm-embedded bacteria. RESULTS: MICs of NAC against 25 A. baumannii isolates ranged from 16 to 128 mg/mL. NAC alone (0.5-128 mg/mL) significantly inhibited biofilm formation and disrupted preformed biofilms. The combination of NAC and TGC induced a partial synergistic effect (60%) and additive effect (28%) on planktonic bacteria. For biofilm-embedded bacteria, treatment with 16 mg/mL NAC alone or 2 µg/mL TGC alone resulted in significant bactericidal effects (P<0.01 and P<0.05, respectively); synergistic bactericidal effect was found at 4 mg/mL NAC combined with 0.5 µg/mL TGC (P<0.01). CONCLUSIONS: NAC alone significantly inhibited biofilm formation of A. baumannii. The combination of NAC and TGC induced partial synergistic effect against planktonic cells and synergistic effect against biofilm-embedded A. baumannii, which might be a therapeutic option for biofilm-related infections of A. baumannii.

Nomogram integrating gene expression signatures with clinicopathological features to predict survival in operable NSCLC: a pooled analysis of 2164 patients.

BACKGROUND: The current tumor-node-metastasis (TNM) staging system is insufficient to predict outcome of patients with operable Non-Small Cell Lung Cancer (NSCLC) owing to its phenotypic and genomic heterogeneity. Integrating genomic signatures with clinicopathological factors may provide more detailed evaluation of prognosis. METHODS: All 2164 clinically annotated NSCLC samples (1326 in the training set and 838 in the validation set) with corresponding microarray data from 17 cohorts were pooled to develop and validate a clinicopathologic-genomic nomogram based on Cox regression model. Two computational methods were applied to these samples to capture expression pattern of genomic signatures representing biological statuses. Model performance was measured by the concordance index (C-index) and calibration plot. Risk group stratification was proposed for the nomogram. RESULTS: Multivariable analysis of the training set identified independent factors including age, TNM stage, combined prognostic classifier, non-overlapping signature, and the ratio of neutrophil to plasma cells. The C-index of the nomogram for predicting survival was statistically superior to that of the TNM stage (training set, 0.686 vs 0.627, respectively; P < .001; validation set, 0.689 vs 0.638, respectively; P < .001). The calibration plots showed that the predicted 1-, 3- and 5-year survival probabilities agreed well with the actual observations. Stratifying patients into three risk groups detected significant differences among survival curves. CONCLUSIONS: These findings offer preliminary evidence that genomic data provide independent and complementary prognostic information and incorporation of this information can refine prognosis in NSCLC. Prospective studies are required to further explore the value of this composite model for prognostic stratification and tailored therapeutic strategies.

PTEN expression is associated with the outcome of lung cancer: evidence from a meta-analysis.

INTRODUCTION: Various studies examined the relationship between the expression of phosphatase and tensin homolog (PTEN) with the clinical outcome in patients with lung cancer, but yielded conflicting results. EVIDENCE ACQUISITION: Electronic databases updated to January 2016 were searched to find relevant studies. A meta-analysis was conducted with eligible studies which quantitatively evaluated the relationship between the expression of PTEN and clinical outcomes of patients with lung cancer. Subgroup and sensitivity analysis were conducted. EVIDENCE SYNTHESIS: A total of 13 studies were included. When compared with high PTEN expression group, the lung cancer patients with reduced PTEN expression exhibited shorter overall survival (hazard ratio=0.40, 95%CI=0.32~0.52, P<0.001) and shorter progression-free survival (hazard ratio=0.53, 95%CI=0.38~0.74, P<0.001). In subgroup analysis, among lung cancer patients whose treatments including EGFR TKIs, we observed significant benefits of OS in high PTEN expression group. CONCLUSIONS: Reduced PTEN expression may be an indicator for poor prognosis in patients with lung cancer. It could have the same influence for patients whose treatments include EGFR-TKIs. The presence of PTEN expression may define a subset of patients with lung cancer appropriate for investigational therapeutic strategies.

TP53 mutation is associated with a poor clinical outcome for non-small cell lung cancer: Evidence from a meta-analysis.

A number of studies have examined the association between tumor protein 53 (TP53) mutations and the clinical outcome in patients with non-small-cell lung cancer (NSCLC), although these have yielded conflicting results. In the present study, electronic databases updated to September 2015 were searched to find relevant studies. A meta-analysis was performed on the eligible studies, which quantitatively evaluated the association between the TP53 mutations and the survival of patients with NSCLC. Subgroup and sensitivity analyses were performed. A total of 19 studies that involved a total of 6,084 patients with NSCLC were included. When the TP53 mutation group (n=1,406) was compared with the wild-type group (lacking TP53 mutations; n=1,965), the wild-type group was associated with a significantly higher overall survival rate [hazard ratio (HR), 1.26; 95% confidence interval (CI) 1.12-1.41, P<0.0001]. Significant benefits of overall survival in the wild-type group were found in the subgroup involving patients with NSCLC in the early stages, including the I/II phases (HR, 1.93, 95% CI, 1.17-3.19, P=0.01; heterogeneity, I2=0.0%, P=0.976) and patients with adenocarcinoma (HR, 3.06; 95% CI, 1.66-5.62, P<0.0001; heterogeneity: I2=0.0%, P=0.976). This meta-analysis has indicated that TP53 gene alteration may be an indicator of a poor prognosis in patients with NSCLC. Furthermore, the results also suggested that the role of TP53 mutations may differ according to different pathological types and clinical stages. The presence of these mutations may define a subset of patients with NSCLC appropriate for investigational therapeutic strategies.